Recurrent CDC25C mutations drive malignant transformation in FPD/AML

被引：66

作者：

Yoshimi, Akihide ^{[1
]}

Toya, Takashi ^{[1
]}

Kawazu, Masahito ^{[2
]}

Ueno, Toshihide ^{[3
]}

Tsukamoto, Ayato ^{[1
]}

Iizuka, Hiromitsu ^{[1
]}

Nakagawa, Masahiro ^{[1
]}

Nannya, Yasuhito ^{[1
]}

Arai, Shunya ^{[1
]}

Harada, Hironori ^{[4
]}

Usuki, Kensuke ^{[5
]}

Hayashi, Yasuhide ^{[6
]}

Ito, Etsuro ^{[7
]}

Kirito, Keita ^{[8
]}

Nakajima, Hideaki ^{[9
]}

Ichikawa, Motoshi ^{[1
]}

Mano, Hiroyuki ^{[3
]}

Kurokawa, Mineo ^{[1
]}

机构：

[1] Univ Tokyo, Grad Sch Med, Dept Hematol & Oncol, Bunkyo Ku, Tokyo 1138655, Japan

[2] Univ Tokyo, Grad Sch Med, Dept Med Genom, Bunkyo Ku, Tokyo 1138655, Japan

[3] Univ Tokyo, Grad Sch Med, Dept Cellular Signaling, Bunkyo Ku, Tokyo 1138655, Japan

[4] Juntendo Univ, Dept Hematol, Sch Med, Bunkyo Ku, Tokyo 1138431, Japan

[5] NTT Med Ctr Tokyo, Dept Hematol, Shinagawa Ku, Tokyo 1418625, Japan

[6] Gunma Childrens Med Ctr, Dept Hematol Oncol, Shibukawa, Gunma 3778577, Japan

[7] Hirosaki Univ, Grad Sch Med, Dept Pediat, Hirosaki, Aomori 0368563, Japan

[8] Univ Yamanashi, Dept Hematol & Oncol, Chuou, Yamanashi 4093898, Japan

[9] Keio Univ, Div Hematol, Dept Internal Med, Sch Med,Shinjyuku Ku, Tokyo 1608582, Japan

来源：

NATURE COMMUNICATIONS | 2014年 / 5卷

关键词：

FAMILIAL PLATELET DISORDER; MYELOID-LEUKEMIA; DNA-DAMAGE; MYELODYSPLASTIC SYNDROME; RUNX1; GATA2; REPAIR; PREDISPOSITION; PROPENSITY; DOMINANT;

D O I：

10.1038/ncomms5770

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Familial platelet disorder (FPD) with predisposition to acute myelogenous leukaemia (AML) is characterized by platelet defects with a propensity for the development of haematological malignancies. Its molecular pathogenesis is poorly understood, except for the role of germline RUNX1 mutations. Here we show that CDC25C mutations are frequently found in FPD/AML patients (53%). Mutated CDC25C disrupts the G2/M checkpoint and promotes cell cycle progression even in the presence of DNA damage, suggesting a critical role for CDC25C in malignant transformation in FPD/AML. The predicted hierarchical architecture shows that CDC25C mutations define a founding pre-leukaemic clone, followed by stepwise acquisition of subclonal mutations that contribute to leukaemia progression. In three of seven individuals with CDC25C mutations, GATA2 is the target of subsequent mutation. Thus, CDC25C is a novel gene target identified in haematological malignancies. CDC25C is also useful as a clinical biomarker that predicts progression of FPD/AML in the early stage.

引用

页数：9

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